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13-02-2024 | Niemann-Pick Disease | Editor's Choice | News

N-acetyl-L-leucine treatment shows phase 3 promise in Niemann–Pick disease type C

Author: Dr. Jonathan Smith


medwireNews: Twelve weeks of treatment with the amino acid analog N-acetyl-l-leucine (NALL) improves the neurologic status of patients with Niemann–Pick disease type C, a phase 3 trial has found.

NALL treatment, when compared with placebo, led to a significant 1.28-point greater reduction in the Assessment and Rating of Ataxia (SARA) score, which ranges from 0 to 40 points, where a lower score means a better neurologic status.

The SARA score decreased by a mean 1.97 points during 12 weeks of NALL treatment, from a mean 15.88 points at baseline, compared with a decrease of 0.60 points from a mean 15.68 points at baseline after the same duration of treatment with placebo.

“Larger and longer studies are required to determine the long-term effect of this agent in patients with Niemann–Pick disease type C,” write Tatiana Bremova-Ertl (University Hospital Bern, Switzerland) and colleagues in The New England Journal of Medicine.

NALL is an oral treatment designed to normalize dysfunctional enzyme-controlled pathways that lead to impaired energy metabolism and lysosomal function in lysosomal storage disorders such as Niemann–Pick disease type C, say the study authors.

The trial was conducted at 13 sites across Australia, the Czech Republic, Germany, the Netherlands, Slovakia, Switzerland, the UK, and the USA. It involved 60 patients aged 4 years and older with genetically confirmed Niemann–Pick disease type C who were randomly assigned to receive either NALL two to three times per day for 12 weeks immediately followed by 12 weeks of placebo, or vice versa. Patients aged between 4 and 12 years received a dose of 2–4 g/day based on bodyweight and those older than 13 years received 4 g/day.

Thirty-eight percent of patients were younger than 18 years, 45% were women, and 90% were White. Niemann–Pick disease type C was most often diagnosed between 6 and 15 years of age (38%), with the mean disease duration being 171.3 months. The majority (85%) of patients were taking miglustat at the time of enrollment and continued to take it for the duration of the trial.

Bremova-Ertl and colleagues note that the SARA scale incorporates assessment of eight items – gait, stance, sitting, and speech disturbance, the finger chase test, the nose-to-finger test, the fast-alternating-hand-movement test, and the heel-along-shin slide test. But for patients from the USA, a modified SARA score excluding the stance and sitting domains was used at the request of the US FDA.

The findings with this modified version were similar to those with the full SARA scale. Scored out of 30, patients had a significantly greater 0.96-point reduction in score when receiving NALL than when receiving placebo, with reductions of 1.66 and 0.67 points, respectively, from corresponding baseline values of 13.20 and 13.03 points.

The researchers note that patients who first received NALL for 12 weeks followed by 12 weeks of placebo saw a worsening of their symptoms when they stopped NALL treatment.

This “suggests that treatment with NALL has an effect on symptoms. However, such deterioration does not establish whether there was a fundamental biologic effect on the disease,” they point out.

The main findings were generally supported by similar trends in the secondary endpoints, including improvements in scores on the Spinocerebellar Ataxia Functional Index, the modified Disability Rating Scale, and the Niemann–Pick Disease Type C Clinical Severity Scale.

There was a similar number of adverse events during NALL treatment (79 events in 36 patients) and placebo treatment (75 events in 30 patients). The researchers found upper respiratory tract infections were more common when patients received NALL than placebo (10 vs 5%), but falls were less common (7 vs 15%). There were no serious treatment-related adverse events or adverse events that led to premature discontinuation of the trial.

In a commentary related to the study, Cynthia Tifft (National Institutes of Health, Bethesda, Maryland, USA) notes that “[if] neuroinflammation is attenuated by treatment with NALL, clinical improvement may be seen in many and perhaps all neurodegenerative lysosomal storage disorders.”

She adds: “As shown in the current study, synergy with other therapies for lysosomal storage disorders would be anticipated.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2024; 390: 421–431
N Engl J Med 2024; 390: 467–470


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